The present invention relates to certain novel beta-amino ethyl-substituted phenyl compounds, especially beta-aminoethoxy-substituted phenyl compounds, which are effective as anti-inflammatory and/or analgesic agents. This invention also relates to methods for synthesizing compounds of the present invention, and intermediates useful in these synthesis methods. The present invention further relates to pharmaceutical compositions containing these compounds, which compositions are useful for treating diseases involving inflammation and/or pain. Finally, the present invention relates to methods for treating diseases characterized by inflammation or pain.
Inflammation, or the "inflammatory response", is the result of complex interconnected physiological events, including increased vascular permeability, fluid accumulations, and the migration of a changing population of inflammatory cells into the inflamed area. The clinical manifestations of inflammation include swelling (edema), increased local temperature, erythema, and pain. The inflammatory response can be triggered by any of a number of causative factors, including certain bacteria, radiation, hypersensitivity to chemical agents, arthritis-like conditions, and the like. The inflammatory response is generally believed to be a primary defense mechanism in the body, but, unchecked, can become excessive and can result in functional impairment.
The use of non-steroidal anti-inflammatory, anti-pyretic and analgesic drugs, especially the salicylates, which include aspirin and aspirin derivatives, to combat inflammation and attendant pain is accepted medical practice. The non-steroidals are commonly employed to relieve pain and inflammation associated with, for example, bursitis, arthritis, and the like.
While pain is incapable of precise definition due to its basically subjective nature, it can generally be said that the term refers to feelings of distress or suffering caused by stimulation of specialized nerve endings. A great variety of drugs have been developed to reduce pain in man and other animals; some directed to eliminating pain at its source, and others directed to blocking the assimilation of pain by the brain. Among the latter group of drugs that are designed to block the sensation of pain, are the analgesics, which generally relieve pain without causing unconsciousness. Analgesics can be further classified in two main categories: opioid analgesics, including morphine, codeine, levorphanol, and the morphine-like analgesics meperidine, and methadone; and antipyretic analgesics, such as aspirin, ibuprofen, phenacetin, acetaminophen, phenylbutazone, and indomethacin.
Although the precise pharmacological action of these analgesics is uncertain, there are certain effects which readily distinguish the opioid analgesics from the antipyretics. In particular, the antipyretics are weak analgesics, with much of their effect in the peripheral nervous system, so that behavioral changes do not usually occur. Generally, these analgesics relieve only somatic pain originating from muscles, joints, tendons and fasciae, and are ineffective against deep visceral pain. However, the opioid analgesics are quite effective against all types of pain, with broad-based action in the central nervous system. Aside from potent analgesia, the opioids, also known as narcotics, often produce effects on mood and other behavioral changes. Perhaps the most notable side effect of the opioid analgesics is the fact that their repeated use is associated with tolerance, as well as psychic and physical dependence.
It has been recently discovered that capsaicin, a natural product of certain species of the genus Capsicium, induces analgesia. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) and "synthetic" capsaicin (N-vanillylnonanamide) are disclosed as analgesics in U.S. Pat. No. 4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicin has also been discussed in the chemical and medical literature, including Yaksh, et al, Science, 206. pp 481-483 (1979); Jancso, et al, Naunyn-Schmiedebero's Arch. Pharmacol., Vol. 311, pp 285-288 (1980) and Holzer et al, Eur. J. Pharm. Vol. 58, pp 511-514 (1979). U.S. Pat. No. 4,238,508, Nelson, issued Dec. 9, 1980, discloses 3-hydroxyacetanilide for use in producing analgesia in animals. European Patent Application 0089710, LaHann, et al, published Sept. 28, 1983, describes hydroxyphenylacetamides with analgesic and anti-irritant activity. Similarly, analgesic and anti-irritant activity is disclosed for N-vanillyl sulfonamides in U.S. Pat. No. 4,401,663, Buckwalter, et al, issued Aug. 30, 1983; hydroxyphenyl-acetamides in U.S. Pat. No. 4,424,205, LaHann, et al, issued Jan. 31, 1984; N-(3- or 4- hydroxy or 3,4-dihydroxybenzyl) carbamates in U.S. Pat. No. 4,443,473, Buckwalter, et al, issued Apr. 17, 1984; N-[(substituted phenyl) methyl]-cis-monounsaturated alkenamides in U.S. Pat. No. 4,493,848, LaHann, et al, issued Jan. 15, 1985; N-(3-methoxy-4-hydroxybenzyl and phenyl) ureas and thioureas in U.S. Pat. No. 4,460,602, Buckwalter, et al, issued July 17, 1984; N-vanillylureas in European Patent Application 0068590, Buckwalter, et al, published Jan. 5, 1983; N-[(substituted phenyl)methyl] alkynamides in U.S. Pat. No. 4,532,139, Janusz, et al, issued July 30, 1985; methylene substituted N-[(substituted phenyl)methyl] alkanamides in U.S. Pat. No. 4,544,668, Janusz, et al, issued Oct. 1, 1985; N-[(substituted phenyl) methyl]-diunsaturated amides in U.S. Pat. No. 4,544,669, LaHann, et al, issued Oct. 1, 1985; monoalkenamides in U.S. Pat. No. 4,564,633, LaHann, et al, issued Jan. 14, 1986; substituted phenylacetic acid esters in British Patent Specification 2,168,974, Loomans, et al, published July 2, 1986; N-(substituted alkyl)alkanamides and thioamides in British Patent Specification 2,168,976, Loomans, et al, published July 2, 1986; substituted aromatic-araalkanamides in British Patent Specification 2,168,975, Janusz et al, published July 2, 1986; combinations of capsaicinoids and arylalkanoic acids in European Patent Application Publication No. 149,545, Brand, published July 24, 1985; combinations of capsaicinoids and opioids in U.S. Pat. No. 4,599,342, LaHann, issued July 8, 1986; European Patent Application Publication No. 187,009, Janusz, et al., published July 9, 1986; European Patent Application Publication No. 206,609, Berman, et al., published Dec. 30, 1986; and beta-aminoethyl-substituted phenyl compounds in European Patent Application No. 282,127, Gardner, et al., published Sept. 14, 1988. The disclosures of all these patent specifications and articles are incorporated herein by reference in their entirety.
Notwithstanding the great effort already put forth to identify anti-inflammatory and analgesic agents, there remains a continuing need to identify new compounds and compositions which are effective for treating inflammation and/or pain. The compounds of the present invention are particularly useful for such purposes since systemic doses of these compounds can be administered to produce general analgesia and anti-inflammatory effects; or local doses can be administered to produce a local analgesic effect similar to that obtained with known local anesthetics. The opiate analgesics an. antipyretic analgesics which are presently widely used for general analgesia are typically not effective via local administration and thus are not generally used as local anesthetics. In addition, the compounds of the present invention are superior to known local anesthetics since they produce analgesia without the loss of mechanical sensation (i.e., "numbing") or motor coordination which are typically observed with the use of known local anesthetics. The properties of the compounds of the present invention therefore make these compounds uniquely suited for local administration before, during and/or after local surgical operations, such as oral surgeries and minor orthopedic surgeries.
An object of the present invention is therefore to provide compounds which can be administered to produce general analgesia and/or anti-inflammatory effects, or can be administered to produce local anesthesia without the associated negatives (e.g., numbness; loss of motor coordination) typically observed with known local anesthetics. Another object of the present invention is to provide compounds which are effective anti-inflammatory and/or analgesic agents, as well as pharmaceutical compositions containing these compounds. It is the further object of the present invention to provide methods for treating diseases characterized by inflammation or pain.
A still further object of the present invention is to provide compounds, and compositions containing these compounds, which have high efficacy, high potency, and/or good therapeutic indices. An additional object is to provide compounds and compositions which cause very little or no skin irritation when administered topically.
In addition, an object of the present invention is to provide compounds which are easily formulated and/or dosed. Another object is to provide compounds which are substantially water soluble. The present invention also relates to methods for synthesizing compounds of the present invention which give high yields and/or which are inexpensive; and to intermediates useful in these synthesis methods.
These and other objects will become readily apparent from the detailed description which follows.
All percentages and ratios used herein are by weight unless otherwise specified.